This is a very well written application that proposes to investigate the relationship between ApoE and AD. Although initial work suggested that the increased risk for AD seen in patients with the apoE4 polymorphism might arise because apo E4 enhances the rate of Abeta aggregation, this work appeared to be flawed because the apoE studied was lipid-free, which does not represent the normal physiological state of the protein. Subsequent work by the investigators and her colleagues suggested that the opposite was actually the case, i.e., that apoE3 and E2 bind better to Abeta than apoE4. This suggests that some other mechanism may account for the increased risk of AD seen in patients with the apoE4 polymorphism. The investigator has now developed a neuronal toxicity assay for Abeta, that she will use in many of the studies in this application. This proposal is designed to test the following hypothesis: that the protection from Abeta-induced neurotoxicity afforded by apoE3 may result from clearance of the peptide via formation of a stable apoE3:Abeta complex and its uptake by apoE receptors. This hypothesis will be investigated via three aims focusing on: (1) the apoE receptors important for attenuating Abeta toxicity, (2) whether apoE/Abeta complexes stimulate or reduce toxicity, and (3) uptake of Abeta in apoE/Abeta complexes.